EP3895713A1 - Procédés permettant de mobiliser des cellules souches - Google Patents

Procédés permettant de mobiliser des cellules souches Download PDF

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EP3895713A1
EP3895713A1 EP21164662.5A EP21164662A EP3895713A1 EP 3895713 A1 EP3895713 A1 EP 3895713A1 EP 21164662 A EP21164662 A EP 21164662A EP 3895713 A1 EP3895713 A1 EP 3895713A1
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stem cells
sel
composition
cells
selectin
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German (de)
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Hsin-Hou Chang
Der-Shan Sun
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Tzu Chi University
Tzu Chi Univ
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Tzu Chi University
Tzu Chi Univ
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0652—Cells of skeletal and connective tissues; Mesenchyme
    • C12N5/0662—Stem cells
    • C12N5/0663—Bone marrow mesenchymal stem cells (BM-MSC)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/28—Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
    • A61K38/178—Lectin superfamily, e.g. selectins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6905—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion
    • A61K47/6911—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion the form being a liposome
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K2035/124—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells the cells being hematopoietic, bone marrow derived or blood cells

Definitions

  • the present disclosure relates generally to methods for inducing mobilization of stem cells for wound healing and/or tissue regeneration applications by administration of a soluble P-selectin.
  • Stem cells are defined as cells with the unique capacity to self-replicate throughout the entire life of an organism and to differentiate into various cell types of the body.
  • Two well-known types of stem cells are embryonic stem cells and adult stem cells. Since stem cells are capable of differentiating into a broad variety of cell types, they play an important role in the wound healing and/or cellular/tissue regenerative processes of various tissues and organs.
  • Some stem cells (such as bone marrow stem cells and hematopoietic stem cells) are released from tissues of origin, and circulate in a subject's circulatory or immune system to migrate into various organs and tissues to become mature, terminally differentiated cells. Therefore, enhancement of stem cell trafficking (i.e., release, circulation, homing and/or migration) can amplify these physiological processes and provide potential therapies for various pathologies.
  • the present disclosure provides a method for mobilizing circulating stem cells in a subject, comprising administering to the subject an amount of a soluble P-selectin (sP-sel) effective to mobilize a population of hematopoietic stem cells or progenitor cells for therapeutic applications.
  • a soluble P-selectin sP-sel
  • the soluble P-selectin can interfere and/or regulate or modulate the interaction between stem cells and niches.
  • the present disclosure provides a composition for use as a medicament for mobilizing circulating stem cells in a subject, wherein the composition comprises an effective amount of a soluble P-selectin (sP-sel) to mobilize the stem cells.
  • sP-sel soluble P-selectin
  • the present disclosure also provides a method for treating a subject in need thereof of preservation, repair, and/or regeneration of a tissue, and/or revascularization in a subject, comprising administering to the subject an amount of a sP-sel effective to mobilize a population of hematopoietic stem cells or progenitor cells. Enhancement of stem cell trafficking (i.e., release, circulation, homing and/or migration) can amplify these physiological processes and provide therapeutic efficacy for various pathologies.
  • the present disclosure also provides a composition for use as a medicament for treating a subject in need thereof of one or more of preservation, and/or repair, and/or regeneration of a tissue, or revascularization in a subject, wherein the composition comprises an effective amount of a sP-sel to mobilize stem cells in the subject.
  • the present disclosure also provides a method of performing an allogeneic hematopoietic stem cell transplant in a patient in need thereof, the method comprising infusing into the patient a therapeutically effective amount of allogeneic hematopoietic stem cells, wherein the hematopoietic stem cells were mobilized from bone marrow of a human donor into peripheral blood of the human donor by a method comprising administering to the donor an effective amount of a sP-sel.
  • the present disclosure also provides a composition for use as a medicament for mobilizing hematopoietic stem cells from bone marrow into peripheral blood of a human donor, wherein the composition comprises an effective amount of a sP-sel to mobilize the hematopoietic stem cells, and the hematopoietic stem cells is used for performing an allogeneic hematopoietic stem cell transplant in a patient in need thereof, and a therapeutically effective amount of allogeneic hematopoietic stem cells is infused into the patient.
  • the stem cells are hematopoietic cells, progenitor cells or bone marrow stem cells.
  • the methods further comprise administering to said subject a second agent prior to, after or concurrently in combination with administering the sP-sel.
  • the second agent is selected from the group consisting of G-CSF, GM-CSF, IL-3, GM-CSF/IL-3 fusion proteins, FLK-2/FLT-3 ligand, stem cell factor, IL-6, IL-11, TPO, VEGF, AMD3100 and combinations thereof.
  • the medicament further comprises a second agent, and the second agent is administrated prior to, after or concurrently with administering the sP-sel.
  • the amount of the sP-sel ranges from about 10 -5 ⁇ g to about 1.5 mg per kg body weight per administration.
  • the sP-sel-mobilized circulating stem cells can produce stem cell derived-extracellular microvesicle.
  • the PselMSCs can ameliorate tissue or organ damage, increase repair, improve glucose tolerance and/or reduce inflammation.
  • the tissue damage is a liver damage.
  • the PselMSCs can repopulate the bone marrow or hematopoietic stem cell population.
  • the PselMSCs can repopulate the bone marrow or hematopoietic stem cell population and rescue tissue injuries, proliferative disorders, inflammatory diseases, immunodeficiency diseases, autoimmune disorders and/or metabolic diseases.
  • the sP-sel is a naturally occurring sP-sel or a recombinant sP-sel.
  • the sP-sel can further conjugate on a vesicle or liposome.
  • the medicament is for interfering in the interaction between stem cells and niches, and/or for producing stem cell derived-extracellular microvesicle by the sP-sel-mobilized circulating stem cells (PselMSCs), and/or for ameliorating tissue or organ damage, increasing repair, improving glucose tolerance and/or reducing inflammation by the PselMSCs and PselMSC-extracellular microvesicles, and/or for repopulating a bone marrow or hematopoietic stem cell population by the PselMSCs, and/or for rescuing tissue injuries, proliferative disorders, inflammatory diseases, immunodeficiency diseases, genetic disorders, degenerative disorders, autoimmune disorders and/or metabolic diseases by the PselMSCs and PselMSC-extracellular microvesicles.
  • PselMSCs sP-sel-mobilized circulating stem cells
  • the present disclosure also provides a method for cell therapy in a subject, comprising administering to the subject an amount of a sP-sel effective to mobilize the stem cells and an amount of stem cells effective to cell therapy.
  • the sP-sel and the stem cells are administered concurrently, separately or intermittently.
  • the medicament further comprises an amount of stem cells.
  • the terms "individual,” “subject,” “host,” and “patient,” refer to a mammal, including, but not limited to, murines (rats, mice), non-human primates, humans, canines, felines, ungulates (e.g., equines, bovines, ovines, porcines, caprines), etc.
  • soluble P-selectin refers to naturally occurring soluble form of P-selectin and recombinant form thereof, or polymorphic or allelic variant or other isoforms thereof.
  • the term also comprises modified or unmodified soluble P-selectin, such as glycosylated or non-glycosylated forms.
  • the terms “mobilize” and “mobilization” refer to processes by which a population of hematopoietic stem or progenitor cells is released from a stem cell niche.
  • the term “niche” refers to the in vivo or in vitro cellular and molecular microenvironments that regulate stem cell function together with stem cell autonomous mechanisms. This includes control of the balance between quiescence, self-renewal, and differentiation, as well as the engagement of specific programs in response to stress.
  • hematopoietic stem cell refers to a stem cell that is capable of differentiating into both myeloid lineages (i.e. monocytes, macrophages, neutrophils, basophils, eosinophils, erythrocytes, megakaryocytes/platelets and some dendritic cells) and lymphoid lineages (i.e. T-cells, B-cells, NK-cells, and some dendritic cells).
  • myeloid lineages i.e. monocytes, macrophages, neutrophils, basophils, eosinophils, erythrocytes, megakaryocytes/platelets and some dendritic cells
  • lymphoid lineages i.e. monocytes, macrophages, neutrophils, basophils, eosinophils, erythrocytes, megakaryocytes/platelets and some dendritic cells
  • lymphoid lineages i.e. T-cell
  • subject refers to any animal, including mammals, birds, reptiles and amphibians and in preferred embodiments to mammals, including humans, companion animals, food production animals and wild animals.
  • the term "donor” refers to a subject from which one or more cells are isolated prior to administration of the cells, or progeny thereof, into a recipient.
  • the term "effective amount" refers to a quantity of one or more agents, such as a quantity of a soluble P-selectin and/or a second agent described herein that mobilizes a population of hematopoietic stem or progenitor cells upon administration to a subject.
  • stem-cell niche (adult or fetal) refers to a microenvironment, within the specific anatomic location where stem cells are found, which interacts with stem cells to regulate cell fate.
  • Stem cells can produce new cells to repair damage to tissues and therefore have great potential for regenerative medicine. However, they exist in small quantities in tissues and especially in peripheral blood, making it difficult to collect them or use them clinically. Mobilization of stem cells is a way to collect stem cells from bone marrow into the blood.
  • a soluble P-selectin sP-sel
  • the mobilization of stem cells with sP-sel can treat a subject in need of one or more of preservation, repair, or regeneration of a tissue, or revascularization in the subject.
  • P-selectin is a member of the selectin family localized in the membranes of ⁇ -granules of platelets and the Weibel-Palade bodies (WP bodies) of endothelial cells. P-selectin is expressed as two different forms; one is the "cell-surface” form and the other is the "soluble” form. The former one is expressed on the activated platelet or endothelial cell that is involved in the inflammation of leukocytes and the homing of HSCs. The latter one (i.e., sP-sel) is almost exclusively expressed in the plasma only during the animal/ human, which is under stress (e.g. hypoxia) ( Chang, H. H. & Sun, D. S.
  • a soluble P-selectin molecule which exists as a monomer in the blood, is 3 kDa smaller than a P-selectin molecule, which exists as an oligomer on a membrane.
  • the soluble P-selectin of healthy individuals originates from the alternatively spliced form found in endothelial cells and platelets.
  • the present invention surprisingly found that treatment of soluble P-selectin may interfere in the interaction between stem cells and niches and thus mobilizes stem cells.
  • the hematopoietic stem and progenitor cells thus mobilized may then be withdrawn from the donor and administered to a patient, where the cells may home to a hematopoietic stem cell niche and re-constitute a population of cells that are damaged or deficient in the patient.
  • sP-sel suitable for mobilization of stem cells
  • examples of the sP-sel of the present disclosure include, but are not limited to, naturally occurring sP-sel and recombinant sP-sel.
  • the sP-sel can be easily obtained by general techniques, such as being isolated from a natural source, purchased from a commercial source, or synthesized with molecular biological techniques.
  • exemplary p-selectin may also include in the alternative, platelet alpha-granule membrane protein, CD62, granulocyte membrane protein; GRMP; and/or GMP140.
  • the sP-sel can be used in combination with a second agent for mobilization of stem cells.
  • the second agent include, but are not limited to, G-CSF, GM-CSF, IL-3, GM-CSF/IL-3 fusion proteins, FLK-2/FLT-3 ligand, stem cell factor, IL-6, IL-11, TPO, VEGF, AMD3100 and combinations thereof.
  • the second agent is G-CSF.
  • the sP-sel and the second agent can be used simultaneously or sequentially.
  • the sP-sel can be used in combination with stem cells.
  • the sP-sel and the stem cells are administered concurrently, separately or intermittently.
  • Hematopoietic stem cell transplant therapy can be administered to a subject in need of treatment so as to populate or repopulate one or more blood cell types, such as a blood cell lineage that is deficient or defective in a patient suffering from a stem cell disorder.
  • Hematopoietic stem and progenitor cells exhibit multi-potency, and can thus differentiate into multiple different blood lineages.
  • Hematopoietic stem cells give rise to different types of blood cells, in lines called myeloid and lymphoid. Myeloid and lymphoid lineages both are involved in dendritic cell formation.
  • Myeloid cells include monocytes, macrophages, neutrophils, basophils, eosinophils, erythrocytes, and megakaryocytes to platelets.
  • Lymphoid cells include T cells, B cells, natural killer cells, and innate lymphoid cells.
  • Hematopoietic stem or progenitor cells mobilized to the peripheral blood of a subject can be withdrawn (e.g., harvested or collected) from the subject by any suitable technique.
  • the hematopoietic stem or progenitor cells may be withdrawn by a blood draw.
  • hematopoietic stem or progenitor cells mobilized to a subject's peripheral blood as contemplated herein may be harvested (i.e., collected) using apheresis.
  • apheresis may be used to enrich a donor's blood with mobilized hematopoietic stem or progenitor cells.
  • the sP-sel disclosed herein can be administered according to various routes of administration, typically by injection, such as local or systemic injection(s). However, other administration routes can be used as well, such as intramuscular, intravenous, intradermic, subcutaneous, etc.
  • the sP-sel is ordinarily combined with one or more adjuvants appropriate for the indicated route of administration. Furthermore, repeated injections can be performed, if needed.
  • the sP-sel is administered in the range of approximately 10 -5 ⁇ g to 1.5 mg per kg body weight.
  • the sP-sel-mobilized circulating stem cells can ameliorate tissue or organ damage, increase repair, improve glucose tolerance and/or reduce inflammation.
  • the PselMSCs also can repopulate the bone marrow or hematopoietic stem cell population and rescue tissue injuries, proliferative disorders, inflammatory diseases, immunodeficiency diseases, genetic disorders, degenerative disorders, autoimmune disorders and/or metabolic diseases.
  • proliferative disorders include, but are not limited to, hematologic cancer and myeloproliferative disease.
  • immunodeficiency diseases include, but are not limited to, congenital immunodeficiency diseases and acquired immunodeficiency diseases.
  • Example of autoimmune disorders include, but are not limited to, juvenile arthritis, ulcerative colitis, Type 1 diabetes mellitus (Type 1 diabetes), multiple sclerosis (MS), inflammatory bowel disease (IBD), psoriasis, psoriatic arthritis, rheumatoid arthritis (RA), human systemic lupus (SLE), autoimmune lymphoproliferative syndrome (ALPS), and lymphocytic colitis.
  • Example of metabolic diseases include, but are not limited to, glycogen storage diseases, mucopolysaccharidoses, Gaucher's Disease, Hurlers Disease, sphingolipidoses, and metachromatic leukodystrophy.
  • Withdrawn hematopoietic stem or progenitor cells may be re-infused into the patient, such that the cells may subsequently home hematopoietic tissue and establish productive hematopoiesis, thereby populating or repopulating a line of cells that is defective or deficient in the patient.
  • mice The recombinant mouse P-selectin (rmP-sel) and granulocyte-colony stimulating factor (G-CSF; Filgrastim®) were injected intravenously per treatment (0.1 mg/kg body weigh) to mice.
  • G-CSF granulocyte-colony stimulating factor
  • Filgrastim® granulocyte-colony stimulating factor
  • G-CSF treatments mobilize CD34 + stem cells, which are able to repopulate the ⁇ -irradiated bone marrow.
  • the LSK hematopoietic stem cell in mice is the cell lineage equivalent to the CD34 + stem cell in human.
  • C57B1/6 recipient mice that had received lethal irradiation with ⁇ -ray were transplanted with 1 x 10 5 LSK cells mobilized with soluble P-selectin ( Fig. 4 ) and G-CSF ( Fig. 5 ).
  • the engraftments are successfully transplanted as revealed by the rescue of 100 % lethal ⁇ -irradiation in mice ( Fig. 5 ; 100 % lethal in non-transplanted groups vs. approximately 83 % survival of both soluble P-selectin mobilized LSK and G-CSF mobilized LSK groups).
  • adipose-derived mesenchymal stem cells may improve glucose homeostasis in high-fat diet-induced obese mice.
  • PselMSCs, PselSCMVs, soluble P-selectin and soluble P-selectin-conjugated liposome remains elusive.
  • Results of glucose tolerance (OGTT) analysis conclusively demonstrated that PselMSCs, PselSCMVs, soluble P-selectin and soluble P-selectin-conjugated liposomes all ameliorated high fat diet (HFD)-induced glucose resistant, whence reduce the blood glucose levels of HFD-mice ( Fig. 7 ).
  • HFD high fat diet
  • Circulating TNF- ⁇ levels which reveal the degree of inflammation, were analyzed in TAA-induced hepatitis mice.

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EP21164662.5A 2020-04-14 2021-03-24 Procédés permettant de mobiliser des cellules souches Pending EP3895713A1 (fr)

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Citations (3)

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Publication number Priority date Publication date Assignee Title
WO2004094619A2 (fr) * 2003-04-18 2004-11-04 Lijun Xia Cellules souches hematopoietiques traitees par fucosylation in vitro et procedes pour les utiliser
US8377887B1 (en) 2003-07-29 2013-02-19 Hsin-Hou Chang Methods of reducing hypoxic stress in a mammal by administering soluble P-selectin
US20180142211A1 (en) 2015-05-20 2018-05-24 Biokine Therapeutics Ltd Methods of mesenchymal stem cell mobilization and expansion

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Publication number Priority date Publication date Assignee Title
EP2961828A4 (fr) * 2013-02-28 2016-08-03 Harvard College Procédés et compositions pour mobiliser des cellules souches
WO2016007506A1 (fr) * 2014-07-07 2016-01-14 Targazyme, Inc. Production et cryopréservation de cellules fucosylées à usage thérapeutique

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004094619A2 (fr) * 2003-04-18 2004-11-04 Lijun Xia Cellules souches hematopoietiques traitees par fucosylation in vitro et procedes pour les utiliser
US8377887B1 (en) 2003-07-29 2013-02-19 Hsin-Hou Chang Methods of reducing hypoxic stress in a mammal by administering soluble P-selectin
US20180142211A1 (en) 2015-05-20 2018-05-24 Biokine Therapeutics Ltd Methods of mesenchymal stem cell mobilization and expansion

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
A BLANN ET AL: "The adhesion molecule P-selectin and cardiovascular disease", EUROPEAN HEART JOURNAL, vol. 24, no. 24, 1 December 2003 (2003-12-01), GB, pages 2166 - 2179, XP055448960, ISSN: 0195-668X, DOI: 10.1016/j.ehj.2003.08.021 *
FRENETTE PAUL S ET AL: "Sulfated glycans induce rapid hematopoietic progenitor cell mobilization: Evidence for selectin-dependent and independent mechanisms", 20001001, vol. 96, no. 7, 1 October 2000 (2000-10-01), pages 2460 - 2468, XP002405544 *
NADAR S K ET AL: "Platelet indexes in relation to target organ damage in high-risk hypertensive patients - A substudy of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)", JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, ELSEVIER, NEW YORK, NY, vol. 44, no. 2, 21 July 2004 (2004-07-21), pages 415 - 422, XP004640848, ISSN: 0735-1097, DOI: 10.1016/J.JACC.2004.03.067 *
TAJIMA, F.SATO, T.LAVER, J. H.OGAWA, M.: "CD34 expression by murine hematopoietic stem cells mobilized by granulocyte colony-stimulating factor", BLOOD, vol. 96, 2000, pages 1989 - 1993

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